Mechanisms of mucosal autoinflammation elucidated by a novel monogenic transcription factor defect

项目摘要 人类先天性免疫缺陷的遗传基础的发现提供了有影响力的信息 关于基因、蛋白质和对健康免疫功能至关重要的途径。炎症 是免疫激活的关键组成部分，其通常发出微生物存在的信号以启动分子免疫。 和细胞反应来控制和消灭病原体。然而，异常高的炎症是 有害于宿主健康并导致一系列人类疾病的病理学。为了控制 在炎症中，有许多细胞内和分泌的抗炎蛋白在细胞中转录- 类型和上下文相关的方式。一个最好的例子是IL-10，当人类有缺陷时， 单基因极早发型IBD然而，关于转录因子的知识相对有限， 作为人类这些诱导型抗炎基因的主要调节因子。我们现在发现了一种新的 ELF 4转录因子基因新的功能缺失突变引起的人类先天性免疫缺陷 我们假设它在干扰素、炎性小体和Th 17的交叉点上起主要调节作用 生物学通过我们的基因组学项目鉴定的三名患者患有粘膜自身炎症， IBD特征，发烧和口腔溃疡，我们现在已经产生了强大的Elf 4敲除，点突变， flozed浮动mouse小鼠models模型to advance推进our knowledge知识.我们在ELF 4突变的人类和小鼠细胞中的初步数据 强调该因子的细胞类型特异性功能，髓系和T细胞中的炎症反应增加， 与失败的抗炎基因表达程序相关的细胞。我们将追求两个目标， ELF 4如何作为干扰素、炎性小体和Th 17应答交叉调节的基石发挥作用。 目的1）研究野生型和突变型ELF 4在髓系和Th 17细胞中的分子生物学效应。目标2） 定义WT和突变型ELF 4在髓系细胞介导的细胞和机体炎症反应中的作用 Th 17细胞这些调查的结果将提供宝贵的新见解， 了解这种新的人类疾病的病因和设计靶向治疗，并通过扩展， 广泛存在于流行的炎症性疾病中。

Project Summary Discovery of the genetic basis of inborn errors of immunity in humans provides impactful information about genes, proteins, and pathways that are fundamentally important for healthy immune function. Inflammation is a critical component of immune activation that normally signals the presence of microbes to initiate molecular and cellular responses required to contain and eliminate a pathogen. However, aberrantly high inflammation is detrimental to host fitness and contributes to pathology in an array of human diseases. In order to control inflammation, there are many intracellular and secreted anti-inflammatory proteins that are transcribed in a cell- type and context-dependent manner. A prime example is IL-10, which when defective in humans causes monogenic very early-onset IBD. However, there is relatively limited knowledge about transcription factors that act as master regulators of these inducible anti-inflammatory genes in humans. We have now discovered a new human inborn error of immunity caused by novel loss-of-function mutations in the ELF4 transcription factor gene that we hypothesize serves as a master regulator at the intersection of interferon, inflammasome, and Th17 biology. The three patients identified through our genomics program suffer from mucosal autoinflammation with IBD features, fever, and oral ulcers, and we have now generated powerful Elf4 knockout, point mutant, and floxed mouse models to advance our knowledge. Our preliminary data in ELF4-mutant human and mouse cells emphasize cell type-specific functions of this factor, with increased inflammatory responses in myeloid and T cells associated with failed anti-inflammatory gene expression programs. We will pursue two aims to illuminate how ELF4 functions as a cornerstone in the cross-regulation of interferon, inflammasome, and Th17 responses. Aim 1) Dissect molecular and biochemical effects of WT and mutant ELF4 in myeloid and Th17 cells. Aim 2) Define the roles of WT and mutant ELF4 in cellular and organismal inflammatory responses mediated by myeloid and Th17 cells. The results of these investigations will provide invaluable new insights with direct relevance for understanding the etiology and devising targeted therapy in this new human disorder and, by extension, more broadly in prevalent inflammatory diseases.